The present invention relates to substituted piperazine derivatives of general formula 
their isomers, their salts, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties.
The compounds of the above general formula I are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma level of the atherogenic lipoproteins.
In the above general formula I
m denotes the number 2 or 3,
n denotes the number 1, 2, 3, 4 or 5,
X denotes a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or Nxe2x80x94(C1-3-alkyl)-imino group,
Ra denotes a bi- or tri-nuclear aromatic hydrocarbon wherein an angular methyne group may be replaced by a nitrogen atom,
a bi- or tri-nuclear heteroaromatic hydrocarbon linked to the piperazino group via a carbon atom, consisting of
a 5-membered heteroaryl ring containing one or two nitrogen atoms and a cyclopentadienyl ring fused on via a vinylene group, wherein additionally a methyne group may be replaced by a nitrogen atom and/or an angular methyne group may be replaced by a nitrogen atom,
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, or an oxygen or sulphur atom, and a phenyl or 6-membered heteroaryl ring fused on via one or two of the available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different, or a naphthyl ring fused on via one of the two available vinylene groups, wherein additionally in a bicyclic or tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom, or
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, or an oxygen or sulphur atom, and one or two nitrogen atoms, and a phenyl, naphthyl, pyridine, pyridazine, pyrimidine or pyrazine ring fused on via the available vinylene group, wherein an angular carbon atom may be replaced by a nitrogen atom,
a naphthyl or 6-membered heteroaryl ring containing one, two or three nitrogen atoms, and a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl ring fused on via a vinylene group,
wherein an angular carbon atom may be replaced by a nitrogen atom, or
a phenyl ring and a 6-membered heteroaryl ring fused on via one or two of the available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different and additionally in a bicyclic or tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom,
a pyridine, pyrazine or pyridazine ring and a phenyl or 6-membered heteroaryl ring fused on via the two available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different and additionally in a tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom,
wherein the bi- and tricyclic groups mentioned above under Ra may additionally be mono- or disubstituted in the carbon skeleton by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or N,N-di-(C1-3-alkyl)-aminocarbonyl group, wherein the substituents may be identical or different and additionally the hydrogen atoms in the abovementioned alkyl and alkoxy moieties may be wholly or partly replaced by fluorine atoms,
Rb and Rc independently of one another in each case denote a hydrogen atom or a C1-3-alkyl group,
Rf and Rg, which may be identical or different, denote hydrogen atoms or C1-6-alkyl groups wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, C3-7-cycloalkyl, phenyl, C1-3-alkoxy-carbonyl-C1-2-alkyl, carboxy-C1-2-alkyl, methoxy-C2-3-alkyl, heteroaryl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl groups,
wherein the abovementioned phenyl and heteroaryl groups may be mono-, di- or tri-substituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by C1-3-alkyl or C1-3-alkoxy groups wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by hydroxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkyl-aminocarbonyl, N,N-di-(C3-alkyl)-aminocarbonyl, N,N-di-(C1-3-alkyl)-amino, nitro or amino groups, wherein the substituents may be identical or different, and/or a hydrogen atom bound to a nitrogen atom of the abovementioned heteroaryl groups may be replaced by a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by a C1-3-alkyl-carbonyl or C1-4-alkoxy-carbonyl group, or
Rf and Rg together with the nitrogen atom between them denote a 3- to 7-membered cycloalkyleneimino group, wherein the methylene group in the 4 position in a 6- or 7-membered cycloalkyleneimino group may additionally be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, imino or N-(C1-3-alkyl)-imino group,
wherein the tricyclic group in the abovementioned general formula I may be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents may be identical or different.
By the rings mentioned above in the definition of the group Ra are meant the aromatic and heteroaromatic bi- and tricycles known from the literature, such as, for example, those described in xe2x80x9cThe Ring Index, Second Edition, A. M. Patterson, L. T. Capell, D. F. Walker, American Chemical Society 1960xe2x80x9d; by a bi-nuclear ring, for example, is meant in particular the naphthyl, pyrrolo-pyrrole, benzofuran, pyrido-furan, pyridazino-furan, pyrimido-furan, pyrazino-furan, benzothiophene, pyrido-thiophene, pyridazino-thiophene, pyrimido-thiophene, pyrazino-thiophene, indole, pyrido-pyrrole, pyridazino-pyrrole, pyrimido-pyrrole, pyrazino-pyrrole, benzo-pyrazole, pyrido-pyrazole, pyridazino-pyrazole, pyrimido-pyrazole, pyrazino-pyrazole, benzotriazole, pyridino-triazole, pyridazino-triazole, pyrimido-triazole, pyrazino-triazole, quinoline, isoquinoline, cinnoline, benzo-pyridazine, quinazoline, benzo-pyrimidine, quinoxaline, benzo-pyrazine, phthalazine, pyrido-pyridine, pyridazino-pyridine, pyrimido-pyridine, pyrazino-pyridine, benzoxazole, pyrido-oxazole, pyridazino-oxazole, pyrimidino-oxazole, pyrazino-oxazole, benzothiazole, pyrido-thiazole, pyridazino-thiazole, pyrimidino-thiazole, pyrazino-thiazole, benzimidazole, pyrido-imidazole, pyridazino-imidazole, pyrimidino-imidazole, pyrazino-imidazole, pteridine, triazolo-pyridine, triazolo-pyridazine, triazolo-pyrimidine, triazolo-pyrazine, pyridazino-pyrimidine, pyrimido-pyrimidine or pteridine ring and
by a tri-nuclear ring is meant the phenanthene, anthracene, dibenzofuran, dibenzothiophene, acridine, phenanthridine, phenanthroline, phenanzine, naphtho-pyrrole, naphtho-pyrazole, naphtho-imidazole, naphtho-pyridine, naphtho-pyridazine, naphtho-pyrimidine or naphtho-pyrazine ring.
Moreover, the saturated alkyl and alkoxy moieties mentioned above in the definition which contain more than 2 carbon atoms also include the branched isomers thereof such as, for example, the isopropyl, tert.butyl, isobutyl group, etc.
Preferred compounds of the above general formula I are those wherein
n denotes the number 3, 4 or 5 and m, X, Ra, Rb, Rc, Rf and Rg are as hereinbefore defined,
the isomers and salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
m denotes the number 2 or 3,
n denotes the number 3, 4 or 5,
X denotes a carbon-carbon bond or an oxygen atom,
Ra denotes a bi- or tri-nuclear aromatic hydrocarbon wherein an angular methyne group may be replaced by a nitrogen atom,
a bi- or tri-nuclear heteroaromatic hydrocarbon linked to the piperazino group via a carbon atom, consisting of
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, or an oxygen or sulphur atom, and a phenyl or 6-membered heteroaryl ring fused on via one or two of the available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different, or a naphthyl ring fused on via one of the two available vinylene groups, wherein additionally in a bicyclic or tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom, or
a 5-membered heteroaryl ring which contains an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group, or an oxygen or sulphur atom, and one or two nitrogen atoms, and a phenyl, naphthyl, pyridine, pyridazine, pyrimidine or pyrazine ring fused on via the available vinylene group, wherein an angular carbon atom may be replaced by a nitrogen atom,
a naphthyl or 6-membered heteroaryl ring containing one, two or three nitrogen atoms, and a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl ring fused on via a vinylene group, wherein an angular carbon atom may be replaced by a nitrogen atom, or
a phenyl ring and a 6-membered heteroaryl ring fused on via one or two of the available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different and additionally in a bicyclic or tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom,
a pyridine, pyrazine or pyridazine ring and a phenyl or 6-membered heteroaryl ring fused on via the two available vinylene groups, containing one, two or three nitrogen atoms, wherein the fused-on rings may be identical or different and additionally in a tricyclic group thus formed an angular carbon atom may be replaced by a nitrogen atom,
wherein the bi- and tricyclic groups mentioned above under Ra may additionally be mono- or disubstituted in the carbon skeleton by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, hydroxy, C1-3-alkoxy, carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or N,N-di-(C1-3-alkyl)-aminocarbonyl group, wherein the substituents may be identical or different and additionally the hydrogen atoms in the abovementioned alkyl and alkoxy moieties may be wholly or partly replaced by fluorine atoms,
Rb and Rc independently of one another each denote a hydrogen atom or a methyl group,
Rf denotes a hydrogen atom, a C1-6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C3-7-cycloalkyl, C1-3-alkoxy-carbonyl-C1-2-alkyl, carboxy-C1-2-alkyl, methoxy-C2-3-alkyl, phenyl, heteroaryl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group,
wherein the abovementioned phenyl and heteroaryl groups may be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine or bromine atoms, by C1-3-alkyl or C1-3-alkoxy groups wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by hydroxy, nitro or amino groups, wherein the substituents may be identical or different, and/or a hydrogen atom bound to a nitrogen atom of the abovementioned heteroaryl groups may be replaced by a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms or by a C1-3-alkyl-carbonyl or C1-4-alkoxy-carbonyl group, and
Rg denotes a hydrogen atom,
wherein the tricyclic group in the abovementioned general formula I may be mono- or disubstituted by fluorine or chlorine atoms or by methyl or methoxy groups and the substituents may be identical or different,
in particular those compounds of general formula I wherein
m denotes the number 2 or 3,
n denotes the number 3, 4 or 5,
X denotes a carbon-carbon bond or an oxygen atom,
Ra denotes a naphthyl, quinolinyl, quinazolinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrido-imidazolyl, pyrimido-imidazolyl, pyrido-pyridinyl or pyrimido-pyrimidinyl group, each of which is connected to the nitrogen atom of the adjacent piperazino group via a carbon atom contained in the bicyclic group, wherein the phenyl moiety of the abovementioned bicyclic groups may be monosubstituted by a trifluoromethyl or nitro group or mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl, methoxy or ethoxy groups, wherein the substituents may be identical or different, and any imino group present in the above-mentioned bicyclic groups may additionally be substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl or pyridyl group,
Rb and Rc independently of one another each denote a hydrogen atom or a methyl group,
Rf denotes a hydrogen atom, a C1-6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C3-7-cycloalkyl, C1-3-alkoxy-carbonyl-C1-2-alkyl, carboxy-C1-2-alkyl, methoxy-C2-3-alkyl, phenyl, heteroaryl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group,
wherein the abovementioned phenyl and heteroaryl groups may each be mono- or disubstituted by fluorine, chlorine or bromine atoms, by C1-3-alkyl or C1-3-alkoxy groups wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, by hydroxy, nitro or amino groups, wherein the substituents may be identical or different, and/or a hydrogen atom bound to a nitrogen atom of the abovementioned heteroaryl groups may be replaced by a C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, or by a C1-3-alkyl-carbonyl group, and
Rg denotes a hydrogen atom,
the isomers and salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
m denotes the number 2,
n denotes the number 4,
X denotes a carbon-carbon bond or an oxygen atom,
Ra denotes a naphthyl, quinolinyl, quinazolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl or pyrido-imidazolyl group each of which is connected to the nitrogen atom of the adjacent piperazino group via a carbon atom contained in the bicyclic group, wherein any imino group present in the above-mentioned bicyclic groups may additionally be substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl or pyridyl group,
Rb and Rc independently of one another each denote a hydrogen atom or a methyl group,
Rf denotes a hydrogen atom, a C1-6-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, a C3-7-cycloalkyl, C1-3-alkoxy-carbonyl-C1-2-alkyl, carboxy-C1-3-alkyl, methoxy-C2-3-alkyl, phenyl, heteroaryl, phenyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group,
wherein the abovementioned phenyl and heteroaryl groups may be substituted in each case by one or two fluorine, chlorine or bromine atoms or by one or two C1-3-alkyl or C1-3-alkoxy groups wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms, and
Rg denotes a hydrogen atom,
the isomers and salts thereof.
According to the invention the new compounds are obtained by methods known from the literature, e.g. by the following methods:
a. Reacting a Compound of General Formula 
wherein
m, Ra, Rb and Rc are as hereinbefore defined, with a compound of general formula 
wherein
n, Rf, Rg, X and the tricyclic ring are as hereinbefore defined and
Z1 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom.
The reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethylsulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium-tert.butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 60xc2x0 C.
b. Reacting a Compound of General Formula 
wherein
m, n, X, Ra, Rb, Rc and the tricyclic ring are as hereinbefore defined, with an amine of general formula 
wherein
Rf and Rg are as hereinbefore defined, or with the reactive derivatives thereof.
The reaction is expediently carried out with a corresponding halide or anhydride of general formula IV in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulpholane optionally in the presence of an inorganic or organic base at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C. It may, however, also be carried out with the free acid optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionylchloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexyl-carbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-thionyldiimidazole or tri-phenylphosphine/carbon tetrachloride, at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
If according to the invention a compound of general formula I is obtained which contains a nitro group, it may be converted by reduction into a corresponding amino compound, or
if a compound of general formula I is obtained which contains an amino or imino group, it may be converted into a corresponding compound by alkylation.
The subsequent reduction of a nitro group is expediently carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as platinum, palladium/charcoal or Raney nickel in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dimethylformamide or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid or hydrochloric acid, with salts such as iron (II) sulphate, tin (II) chloride, sodium sulphide, sodium hydrogen sulphite or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 100xc2x0 C., but preferably at temperatures between 20 and 60xc2x0 C.
The subsequent alkylation is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane, dimethylsulphoxide or sulpholane with an alkylating agent such as a corresponding halide or sulphonic acid ester, e.g. with methyl iodide, ethyl bromide, dimethylsulphate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, expediently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, tert.butyl-dimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120xc2x0 C., preferably at temperatures between 10 and 100xc2x0 C. However, a silyl group may also be cleaved using tetrabutylammonium fluoride as described hereinbefore.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100xc2x0 C., but preferably at temperatures between 20 and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120xc2x0 C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50xc2x0 C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I thus obtained contain an acidic group such as a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
The compounds of general formulae II to V used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature or are described in the Examples.
A compound of general formula II is obtained for example by reacting a compound of general formula Raxe2x80x2xe2x80x94Cl with a corresponding piperazine or homopiperazine wherein an imino group is substituted by the group Z2 wherein Z2 denotes a hydrogen atom or a protecting group for an amino group, for example the tert.butoxycarbonyl or benzyloxycarbonyl group, in a melt or in a solvent such as ethanol, dioxane or dimethylformamide in the presence of a base such as triethylamine and at temperatures between 0 and 130xc2x0 C. The protecting group is cleaved by methods known from the literature and leads to a compound of general formula II.
A compound of general formula III is obtained for example by reacting a corresponding disubstituted carboxylic acid with a xcex1,xcfx89-dihaloalkane in the presence of a strong base such as lithium diisopropylamide, sodium amide or sodium hydride and subsequently reacting the carboxylic acid with a corresponding amine.
A compound of general formula IV is expediently obtained by reacting a correspondingly protected carboxylic acid derivative with a corresponding piperazine or homopiperazine.
As already mentioned hereinbefore, the compounds of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. In particular, they are valuable inhibitors of the microsomal triglyceride-transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
For example, the compounds according to the invention were investigated for their biological effects as follows:
Inhibitors of MTP were identified by a cell-free MTP activity test. Solubilised liver microsomes from various species (e.g. rat, pig) can be used as the MTP source. To prepare the donor and acceptor vesicles, lipids dissolved in organic solvents were mixed in a suitable ratio and applied as a thin layer to the wall of glass container by blowing the solvent in a nitrogen current. The solution used to prepare donor vesicles contained 400 xcexcM of phosphatidyl choline, 75 xcexcM of cardiolipin and 10 xcexcM of [14C]-triolein (68.8 xcexcCi/mg). To prepare the acceptor vesicles, a solution of 1.2 mM phosphatidyl choline, 5 xcexcM triolein and 15 xcexcM [3H]-dipalmitoylphosphatidyl choline (108 mCi/mg) was used. Vesicles are produced by wetting the dried lipids with test buffer and subsequently ultrasonicating. Vesicle populations of uniform size were obtained by gel filtration of the ultrasonicated lipids. The MTP activity test contains donor vesicles, acceptor vesicles as well as the MTP source in test buffer. Substances were added from concentrated DMSO-containing stock solutions, the final concentration of DMSO in the test was 0.1%. The reaction was started by the addition of MTP. After a corresponding incubation time the transfer process was stopped by the addition of 500 xcexcl of a SOURCE 30Q anion exchanger suspension (Pharmacia Biotech). The mixture was shaken for 5 minutes and the donor vesicles bound to the anion exchanger material were separated off by centrifuging. The radioactivity of [3H] and [14C] in the supernatant was determined by liquid scintillation measurement and from this the recovery of the acceptor vesicles and the triglyceride transfer speed was calculated.
In view of the abovementioned biological properties the compounds of general formula I and the physiologically acceptable salts thereof are particularly suitable for lowering the plasma concentration of atherogenic apolipoprotein B (apoB)-containing lipoproteins such as chylomicrons and/or very low density lipoproteins (VLDL) as well as the residues thereof such as low density lipoproteins (LDL) and/or lipoprotein(a) (Lp(a)), for treating hyperlipidaemias, for preventing and treating atherosclerosis and the clinical sequelae thereof, and for preventing and treating related disorders such as diabetes mellitus, adiposity and pancreatitis, oral administration being preferred.
The daily dose needed to achieve such an effect is between 0.5 and 500 mg, expediently between 1 and 350 mg, but preferably between 5 and 200 mg, in adults.
For this purpose, the compounds of formula I prepared according to the invention, optionally combined with other active substances such as other lipid-lowering agents, for example HMG-CoA-reductase-inhibitors, cholesterol biosynthesis inhibitors such as squalene synthase inhibitors and squalene cyclase inhibitors, bile acid-binding resins, fibrates, cholesterol resorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The Examples which follow are intended to illustrate the invention in more detail: